The invention relates to compositions that are used in methods of deforming a selected tissue structure for treatment of e.g., incontinence, vesicoureteral reflux, or gastroesophageal reflux.
In the recent past, urinary incontinence has been successfully treated by using minimally invasive surgical means. One method which has been used to treat patients with urinary incontinence is periurethral or transurethral injection of a composition commercially sold in Canada as xe2x80x9cPolytefxe2x80x9d and as xe2x80x9cUrethrin.xe2x80x9d xe2x80x9cPolytefxe2x80x9d is a paste comprising a fifty-fifty (50/50) by weight mixture of glycerine liquid and PTFE particles. However, after injection, over a period of time the glycerin is readily dissipated into the body and then metabolized or eliminated, leaving only the PTFE particles. This means that only fifty (50) percent of the injected weight remains at the injection site. Consequently the surgeon must inject significantly more volume than necessary and at times may inadvertently coapt the urethra further than is desired. This closure could possibly be complete and thus place the patient into temporary urinary retention. Additionally, the fact that a large portion of the injected volume disappears makes it difficult for the surgeon to visually gauge how much is an appropriate amount of the PTFE paste to inject. As a result, the surgeon is likely not to inject enough paste volume. The procedure therefore may fail, and multiple procedures to inject additional paste may be required. An additional drawback of the PTFE paste is that the PTFE particle size is sufficiently small so as to allow the particles to migrate to other locations of the body such as the lungs, brain, etc. PTFE particles have been known to induce tissue reaction and form PTFE-induced granulomas in certain individuals. This tissue reaction to PTFE has caused concerns for the patient""s safety. Also, the PTFE paste is highly viscous and can only be injected by applying a large injection force (IF). Often this is accomplished by utilizing an injection assist device in order to deliver the highly viscous PTFE paste through a needle of any acceptable size at acceptable flow rates.
An alternative to using the PTFE paste is using a collagen suspension. The collagen suspension is injected in the same manner as PTFE paste so as to form a fibrous mass of tissue around the augmentation site. This fibrous mass created by the collagen injection, however, decreases in size and breaks down over time as it is eventually degraded by the patient""s body. As a result, additional injections are periodically required.
Another alternative is to inject silicone particles dispersed in an aqueous, polyvinylpyrrolidone (PVP) solution. This combination has the same problems as the PTFE paste, in that the polyvinylpyrrolidone solution is readily dissipated away from the area of injection, leaving only the volume of silicone particles remaining and, in that, due to its high viscosity, a great deal of force is necessary to inject the silicone dispersion through a needle of an acceptable size, whereby it is necessary for the surgeon to utilize an injection assist device to accomplish injection.
Another material that has been injected is autologous fat. This has had similar problems as the collagen, in that the body eventually breaks it down and it disappears. The act of harvesting the autologous fat and processing it for injection is also time consuming and provides variable levels of clinical improvement.
Devices have been made to attempt to overcome these problems. One device is an inflatable silicone sphere that is passed through a needle and is inflated with PVP in the same area that the other materials are injected. There are, however, some problems associated with this device. It is a delicate, mechanical device that is capable of mechanical failure of the valves, shells and structural joints. Also disadvantageous are the fixed geometry of the sphere, potential migration along the implantation tract, or extrusion of the device through the periurethral tissues.
Hydrogel particles provide desirable mechanical and tissue response properties; however they need to be resuspended in a nonaqueous carrier for injection. This allows for easy injection of small, dehydrated particles, which can later swell, in-situ following clearance of the carrier. These injectable suspensions suffer from the defect of particle settling and separation as the composition is stored for long periods of time. The settling is driven by the inherent density differences between particles and carrier. This phenomenon requires that the suspension therefore either be mixed or remixed at the time of use to obtain a uniform suspension at the time of injection. The mixing requirement is both inconvenient, can necessitate the need for additional equipment, and if not performed thoroughly can lead to uneven placement of particles when inserted into tissues, therefore possibly providing a poor procedure result. Also disadvantageous is the potential for the settled particles to clog the needle during injection. Berg, et al., in U.S. Pat. No. 5,007,940 have made an attempt to overcome the problems enumerated above by utilizing densely packed, fully hydrated hydrogel particles in disk form which deform as they pass through a needle during injection. The dense packing of the particles eliminates problems of particle settling since neighboring particles touch each other and thereby support the weight of particles above them. This art teaches that the deformability of hydrogel particles is sufficient to allow injection with dense packing (i.e., no free carrier liquid). The manufacture of the particles described in patent #5,007,940 is complex and costly and they have not been utilized commercially. Also the densely packed particles, despite their high degree of deformability, have still exhibited a relatively high viscosity whereby their use has required the use of relatively large internal diameter needles and the use of relatively large injection forces to accomplish insertion in a patient.
Van Bladel et al., in U.S. Pat. No. 5,813,411 disclose that injection of a densely packed suspension of hydrogel particles is made easier when an organic agent is added to the aqueous liquid swelling the particles. Our attempts to practice this embodiment, without the incorporation of excess suspending liquid have still presented several challenges. Most significantly, the organic additives dehydrate and shrink the particles, yet upon clearance of the dehydrating organic in the body the implant will swell to a volume larger than what was originally injected. This can cause serious problems in urethral augmentation where the additional swelling of the implant can cause closure of the urethra leading to difficulty in urination or even retention. In addition, high stresses exerted on densely packed particles as they are forced into the hub of needles during the injection process can lead to particle fracture. This is particularly significant for highly swollen hydrogels and for those exhibiting brittleness. Further dehydration of the particles by the addition of more organic either leads to particle settling when the particles become severely dehydrated or exacerbates the excess in-situ swelling of the implant or increases to required injection force. The settling also increases the opportunity of needle clogging during implantation.
Wallace et al., in U.S. Pat. No. 4,803,075 teach the addition of a polymer lubricant to an aqueous suspension of particles to reduce injection forces for injectable particulate soft tissue bulking agents. This additive to a carrier liquid does not prevent settling of particles from solution during storage and hence can still require remixing a suspension at the time of use.
Accordingly, it would be desirable to have a composition that is ready to inject at the time of use, without having to reconstitute it or use an injection assist device to inject it. Also, it would be desirable to have a composition that will not change in volume following injection, that will be soft enough so as not to cause tissue response/reaction, while still being firm enough to provide the required constriction, and that will not dissipate or migrate from the site of injection, thereby enabling the urethra to maintain the initial surgical coaptation.
The present invention provides a composition and method for augmenting, or deforming, soft tissue. The composition comprises a continuous carrier comprising an aqueous solvent having dissolved therein a hydrogel and a dehydrating agent, wherein said continuous phase is a solid at temperatures less than about 10xc2x0 C. or greater than about 30xc2x0 C. and is a fluid at temperatures between about 10xc2x0 C. and about 30xc2x0 C.; and a discontinuous phase comprising a plurality of hydrophilic hydrogel particles that are swellable in said aqueous solvent, that are not biodegradable for periods of time in excess of one year, and that have a hydrated diameter of greater than about 25 microns upon hydration by physiologic fluid, wherein a final volume of said hydrophilic hydrogel particles upon hydration by physiologic fluid is substantially the same as an initial volume of said composition.
Compositions of the present invention comprise a continuous carrier phase and a discontinuous bulking phase. The discontinuous bulking phase comprises discrete, swellable, hydrophilic hydrogel particles. By swellable, it is meant that the hydrogel bulking particles are substantially insoluble in the aqueous solvent of the continuous phase, but will swell upon injection into soft tissue due to hydration by physiologic fluid from an initial dehydrated volume to a final hydrated volume that is substantially the same as the initial total volume of composition injected into the tissue to be augmented. The hydrogel bulking particles must be of a chemical composition such that they will not be broken down in the patient""s body, i.e., biodegraded, for periods of time in excess of one year.
The continuous phase comprises a hydrogel carrier that is a solid, i.e., non-pouring or non-flowing, under storage conditions, e.g., under refrigeration, but becomes a pourable fluid at temperatures where the composition is to be used, e.g., at room temperature. Preferably, the hydrogel carrier is a solid at temperatures less than about 10xc2x0 C. and greater than about 30xc2x0 C., but becomes fluid at temperatures between about 10xc2x0 C. and 30xc2x0 C. The dehydrating agent is dissolved in the aqueous solvent and serves to dehydrate the hydrophilic hydrogel bulking particle. It is essential to the invention that the aqueous solvent used in the continuous phase is one in which both the hydrogel carrier is soluble and the hydrogel bulking particles are swellable.
The method of augmenting soft tissues comprises injecting a predetermined volume of the composition directly into the tissue sites requiring augmentation, e.g., bulking. The volume of the injection is injected such that coaptation of the urethral tissue is achieved. Following implantation of the composition, the hydrogel carrier and dehydrating agent are cleared by the body within six months and the hydrophilic hydrogel bulking particles remain behind to provide durable bulking. The ratio of the hydrogel carrier:dehydrating agent:hydrogel bulking particles is selected such that the final hydrated volume of hydrogel bulking particles, once hydrated with physiologic fluid, closely approximates the initial volume of composition injected into the tissue site. This is due to the use of the dehydrating agent in relative amounts effective to shrink the hydrophilic hydrogel bulking particles to a dehydrated state, relative to their hydrated volume in physiologic fluid. The mass of hydrophilic hydrogel bulking particles therefore is selected such that upon clearance of the hydrogel carrier and dehydrating agent from the site of implantation, the hydrogel bulking particles swell to replace the volume of carrier and dehydrating agent that clears the implantation site. This concept is termed a xe2x80x9ccontrolled volumexe2x80x9d injection.
The present invention provides three significant benefits over conventional augmentation compositions. First, it provides the benefit of low irritation and a good tissue mechanical compliance match through the use of hydrogel particles as the durable bulking agent. Second, the use of a hydrogel carrier that is solid under storage conditions provides the benefit of shelf stability. For example, there is no need to remix the composition at the time of use due to separation of the continuous and discontinuous phases. Thirdly, the dehydrating agent provides the benefits of easier injection into tissue, since hydrogel particle size is reduced via dehydration, and, more importantly, provides an implant that closely approximates the initial volume of composition injected. This xe2x80x9cvolume retentionxe2x80x9d property contrasts conventional injectable collagen, PTFE and silicone suspensions that provide final implanted volumes, i.e., after the respective carrier clears the sites of implantation, that are less than the initial volume of composition injected into the tissue site
The hydrophilic hydrogel bulking particles, depending on the degree of dehydration, retain significant deformability so long as they retain some water. Very rigid or non-deformable particles can become difficult to inject and lead to needle clogging. It is essential that the degree of dehydration of the hydrogel bulking particles be selected to balance the benefit of reduced hydrogel particle size against the detriment of more rigid, non-deformable particles, as each property affects injectability of the dehydrated hydrogel particles. This is accomplished by utilizing an amount of dehydrating agent that is effective to provide the appropriate balance of properties.
The hydrophilic hydrogel bulking particles comprise a hydrophilic polymer network that is swellable in aqueous media. The particles are hydrophilic and absorb at least 20% of their dry mass in water, preferably over 100%. The particles are processed so as to be greater than about 25 microns in diameter in their fully hydrated state, preferably greater than 50 microns in diameter. The particles can be irregularly shaped. Hence, the diameters refer to equivalent lengths that describe the largest single dimension of particle size. It will be understood by those with ordinary skill in the art that in actual preparations there may be traces of particles outside of this size range.
Possible polymers that may be used as hydrophilic hydrogel bulking particles may be selected from the group consisting of polyethylene oxides, polypropylene oxides, polyvinyl alcohols, polyvinylpyrrolidones, polyethylene imines, polyacrylamides, polyacrylonitriles, polyHEMA polymers, Hypan polymers, starch glycolate polymers, crosslinked, acrylic acid-based polymers, (e.g., Carbopol, BFGoodrich, Charlotte, N.C.), carbohydrates and proteins. It will also be understood that derivatives of such polymers, copolymers, and/or blends or mixtures of the various polymer families may be used in this invention.
Preferred hydrogel bulking particles include radiation cross-linked polyvinylpyrrolidone (PVP). PVP is non-toxic and biocompatible. Cross-linked PVP is not known to be biodegradable and thus PVP hydrogel particles would provide bulking properties in excess of one year. While PVP in general is used in parenteral application in many medical devices and pharmaceutical formulations, we have found that PVP of a particular molecular weight range and irradiated to a particular radiation dosage exposure provides unique benefits over conventional cross-linked PVP. The use of a radiation dosage range between 5 and 7 mRAD with PVP molecular weights between 20,000 and 100,000 daltons produces a gel of optimum toughness. The lower radiation dosage range of from 2.5 to 3.3 mRAD leads to gels that are fluid and very weak. Therefore, gels cross-linked at such lower radiation dosage, while directly injectable, do not provide durable clinical correction of tissues into which they are inserted. Additionally, we have found that PVP having molecular weight over 1,000,000 daltons and being cross-linked at a radiation dosage of 10 mRAD leads to very brittle particles that are friable. The friability of these particles is problematic, since the smaller particles of PVP produced can be endocytized by cells and transported to other sites in the body.
As the composition implant is expected to provide long term tissue bulking, optimal mechanical toughness is a key physical property. When cross-linking is performed at PVP concentrations above 40% (w/w), the resulting particles, when allowed to fully hydrate, swell to such an extent that they crack and either fragment into microparticles or become mechanically weak. The preferred PVP concentration range for cross-linking is 10-20% (w/w), which produces the toughest particles in the hydrated state. It is desirable to inject the particles in a partially hydrated state since they soften upon swelling with aqueous medium. The enhanced deformability imparted to the particles in the swollen state facilitates the injection process, allowing reduced injection forces to be applied, as well as producing less trauma when the implant intrudes into injected tissues.
Dehydrating agents must be capable of shrinking the fully swollen hydrogel in physiologic medium. They must also be physiologically acceptable and capable of being cleared over time by convective, diffusional and metabolic processes normally active in body tissues. They can include organic and inorganic molecules. The dehydrating agent, at physiologically acceptable concentrations, must be capable of shrinking a fully hydrated particle by at least 10% of its volume. Examples of organic molecules that may be used as dehydrating agents with PVP hydrogel bulking particles of the present invention include polyethylene glycol, hydrophilic carbohydrates, alcohols and proteins. Inorganic salts, such as sodium carbonate or sodium phosphates, also may be used to dehydrate PVP gels. A preferred dehydrating agent is polyethylene glycol (PEG). At concentrations as low as 3% (w/w), 3,400 dalton PEG was able to shrink PVP gels by 10% in volume and at 5% concentration was able to shrink the gel by 20% in volume.
The hydrogel bulking particles are suspended in the continuous phase comprising the hydrogel carrier and the composition is packaged in a sterile syringe. As described herein, compositions according to the present invention are shelf stable, i.e., the hydrogel bulking particles do not settle out of the continuous phase comprising the hydrogel carrier upon storage. The compositions contain a uniform distribution of hydrogel bulking particles, produce a controlled volume implant and provide for injection, through acceptable needle diameters and at acceptable flow rates, with manually generated forces of less than 20 pounds, preferably of less than 10 pounds.
The benefit of shelf stability is that clinicians can directly inject the composition without further preparation, e.g., defrosting of a frozen composition, reconstitution, or mixing. This reduces procedure time and provides good assurance of sterility, as well as consistent results. Suspending the partially hydrated particles in a liquid carrier provides the desired implant volume and injection characteristics; however, the particles settle in the syringe during storage and consequently must be remixed prior to use. It was found that freezing an aqueous liquid carrier could provide shelf stability and then could be thawed and injected without further preparation. However, this is undesirable for several reasons, including that the frozen carrier required excessive time to thaw, that the particles were sometimes damaged by the expansion and contraction they were subjected to during the freezing and melting process, and that the cost and inconvenience of shipping a frozen product is prohibitive.
Surprisingly, we found that it was possible to produce carriers that could be solid, and hence shelf-stable, slightly below room temperature, and that could be rendered fluid quickly, e.g., within a few minutes, and injectable when brought to room temperature. The term solid carrier, as used herein, means those carriers that, when no deforming stresses are present and at appropriate temperatures, will suspend hydrogel bulking particles without settling for periods of over one year. The carrier also should be cleared rapidly from the body and be physiologically acceptable. Preferred carriers are soft solid hydrogels which can be made firm when refrigerated and which become soft enough to be injected when warmed a few degrees. Preferably the carrier should form a solid at 10xc2x0 C. and be readily injectable at temperatures above 15xc2x0 C. It should be noted that gels that become solid at temperatures above room temperature and that soften when cooled slightly (reverse thermal gels) also are included in the scope of this invention. Reverse thermal solid carriers would need to be stored above room temperature and then cooled at the time of use. Examples of polymers which are reverse thermal gels include polyethylene glycol-polypropylene glycol copolymers, which are available commercially from BASF, Mount Olive, N.J., under the trade name Pluronics. Examples of polymers exhibiting thermal gelation include polyvinyl alcohol derivatives, proteins and carbohydrates. Preferred are gelatin and iron complexed hyaluronic acid.
Gelatin is formed from denatured fibrillar collagen or tissues and can include raw material from animal, cadaver or recombinant sources. It will also be understood by those with ordinary skill in the art that other proteins and carbohydrates can be included in specific gelatin compositions. It is well established that gelatin is rapidly degraded by enzymes in the body and clears quickly following implantation.
Aqueous gelatin solutions above a critical concentration become insoluble as temperatures are reduced below 37xc2x0 C. and can become solid below 10xc2x0 C. This process is reversible which is a critical feature of this invention. We have found that the presence of a dehydrating agent in a gelatin solution can significantly affect its solidifying properties. Consequently, specific concentration ranges for gelatin must be selected in concert with the dehydrating agent being used. Outside of this range the benefits of rapid solidification and fluidizing within a narrow temperature range might not occur. PEG tends to make gelatin form a softer gel or requires higher gelatin concentrations to form a gel of similar firmness. At concentrations above 40% PEG we found that it was impossible to form a gelatin solid at any temperature. Hence it is critical that the dehydrating agent be present at concentrations which permit the carrier to solidify. The preferred PEG concentration range is between about 3 and about 10% with gelatin concentrations between about 1 to about 10%. Within this range there is significant shrinkage of PVP particles, yet the carrier forms a solid below 10xc2x0 C. Gelatin at concentrations below about 1% in the presence of PEG (at concentrations above about 3%) did not form a solid at temperatures above 0xc2x0 C. Above about 15xc2x0 C., the carrier, in the desired compositional range, softens sufficiently to be easily injected. At gelatin concentrations above about 10%, the softening required for manual injection required warming to temperatures well above room temperature (20xc2x0 C.). In the desired composition range, the mechanical transition occurs very rapidly at temperatures above about 15xc2x0 C. and can be accomplished within a couple of minutes by grasping a syringe of 1 cm diameter or less in a human closed hand. The process requires a few more minutes if the syringe is simply allowed to sit at room temperature. We have found that at 20xc2x0 C. there is no observable particle settling for periods of several days, thereby allowing sufficient time for injection following warming, without particle settling occurring.